Platinum complexes, in particular diamine-based platinum complexes such as cisplatin, carboplatin, and oxaliplatin, are an important class of anti-cancer agents, which have been widely used for treating cancers such as ovarian, testicular, small cell lung, and colorectal cancers.
With the increasing cisplatin/carboplatin-resistance of cancers, for example, ovarian cancer, there have been efforts within industry to replace cisplatin/carboplatin with more effective, less-resistant chemotherapeutics, for example platinum oxalate, platinum phosphate and/or pyrophosphate complexes. However, not until recent years did platinum phosphate or pyrophosphate complexes gain importance in their potential as cancer-treating agents, partly because these complexes are prone to form insoluble phosphate-bridged dinuclear complexes. Although some dinuclear phosphatoplatinum complexes were reported to possess excellent anticancer properties, further exploration of their applications as well as their syntheses were limited because of the poor solubility of these complexes in aqueous solutions. Although certain monomeric pyro- and triphosphate platinum complexes were known in the art, they were not suitable for pharmaceutical compositions because they would undergo phosphate hydrolysis in moderately acidic solutions to become insoluble dinuclear products (see Bose et al., Inorg. Chem., 1985, 24, 3989-3996; and U.S. Pat. No. 7,342,122 and WO 2005/000858 to Odani et al., which are hereby incorporated by reference).
U.S. Pat. Nos. 7,700,649 and 8,034,964 (both to Bose), which are both incorporated by reference (the “Bose patents”), disclose synthetic routes and treatment methods involving a new class of platinum complexes, namely monomeric amine or diamine platinum pyrophosphate complexes. Among the pyrophosphato-platinum complexes disclosed in Bose patents are the amine or diamine platinum pyrophosphate complexes shown in FIG. 1. These complexes were found efficacious in the treatment of various cancers, including cisplatin and carboplatin-resistant cancers. However, until the present invention, syntheses of these compounds remained inefficient, and a process suitable for large-scale preparation of these complexes has not been reported. Various factors, for example, the sensitivity of the monomeric complexes to synthetic conditions, and their tendency to form dinuclear counterparts under certain conditions, make large-scale preparation and purification of these monomeric complexes a challenge.